臺灣博碩士論文加值系統

中文摘要:
顯微手術技術已廣泛運用在移植組織重建手術上，而血管栓塞與組織缺氧損傷為影響移植組織存活主因。血小板活化凝集在血管吻合血栓形成與組織缺氧壞死扮演重要角色。然而對於血小板增多與血栓形成相關性仍有爭議。基於臨床觀察，我們利用一老鼠血小板增多模型(脾臟切除引發次發性血小板增多症)及一血管內皮細胞受損模型(股動脈截斷面部分動脈外膜反向縫合造成血管腔內形成血栓性外膜)來探討血小板數量與活化和內皮細胞受損對顯微血管血栓形成間扮演相關角色為何。我們進一步嘗試研究血小板活化與組織缺氧再灌注後自由基釋放對顯微皮瓣組織手術成功失敗相關性為何；更評估是否血小板活化進而沉積在內皮細胞上導致移植皮瓣組織失敗。我們利用一老鼠下腹壁動脈血管莖皮瓣模型，評估嘗試利用血小板膜糖蛋白GP IIb/IIIa接受體拮抗劑 (如abciximab)，可否降低血小板活化，以增高移植皮瓣成功率。除了膜糖蛋白分子可能與組織存活有關外，我們也研究一氧化氮(nitric oxide, NO)是否可降低血小板活化並保護內皮細胞及皮瓣組織的存活。我們評估給予一氧化氮供應者，nitrosoglutathione (GSNO)可否有效抑制血小板活化，並調控血小板NO synthase (NOS) 活性，以提高皮瓣組織再灌注成功率。研究也針對NO其本身對調節血管張力及內皮細胞受損導致不同NOS亞型種類變化和皮瓣組織存活的角色進行研究。我們評估給予NO供應者是否亦經由調控氧化壓力的基因轉譯核因子NF-kB活化及iNOS的作用而促進皮瓣再灌注的成功率。研究結果發現單純血小板增多不會影響血管吻合皮瓣存活率。但如果合併血管內皮細胞受損，易引發血小板活化及血管血栓形成導致吻合成功率降低。血小板活化有參與皮瓣組織經缺氧再灌注損傷導致組織壞死；使用血小板活化抑制劑abciximab可明顯抑制血小板活化/凝集，進而促進皮瓣再灌注後成功率。給予適量NO供應者GSNO可明顯抑制組織再灌注造成之血小板活化；調控血小板及血管莖內皮細胞NOS表現(eNOS增多，iNOS減少)，而提高皮瓣血流速度進而提高皮瓣組織成功率。追蹤其原因發現GSNO與抗氧化劑N-acetylcysteine (NAC)似有類同之處，先是抑制血管內皮細胞superoxide產生和核因子NF-kB活化，進而減少iNOS及3-nitro-tyrosine表現；並促進血液流通，導致較佳皮瓣存活率。這些研究結果顯示，顯微血管皮瓣組織移植重建後產生的血液再灌注損傷和皮瓣死亡可以因不同血小板拮抗劑的使用獲得顯著改善。

英文摘要
Despite advances in microsurgical technique and experience gained in clinical vascular surgery, vascular thrombosis and ischemic necrosis remained the most significant threat to flap survival. Evidence has shown that platelets play an important role in the pathogenesis of flap failure. There is still controversial about the correlation of thrombocytosis and thrombosis complication. Employing a rodent splenectomy-induced thrombocytosis model and a thrombogenic endothelial damage model, we investigated whether thrombocytosis or platelet activation with or without endothelial damage contributes to microvascular thrombosis. We further investigated whether platelet activation and deposition on flap vessels was involved in skin flap failure by using an inferior epigastric artery skin flap as a flap tissue ischemia/reperfusion (I/R) injury model. Additionally, platelet receptor antagonist, abciximab (chimeric 7E3 Fab), was used to explore the roles of platelet activation on the flap survival. Administration of nitric oxide (NO) donor, nitrosoglutathione (GSNO), and NO synthase (NOS) inhibitor was also used to investigate the roles of NO and NOS expression in platelets and pedicle endothelium for promoting flap tissue survival after I/R injury. Results showed that microvascular anastomosis could be performed safely under reactive thrombocytosis alone without platelet activation. Platelet activation was more critical than increase of platelet counts in microvascular anastomosis. The activation of platelets as demonstrated by CD62P progressively increased after flap tissue reperfusion. Blockade of platelet activation/aggregation by abciximab had a positive effect on flap survival and decrease of activated-platelet deposition on vascular endothelium. NO donor, GSNO, suppressed platelet activation and iNOS induction of platelet and flap vessels, resulting in less platelet activation, better blood perfusion and flap survival after I/R injury. GSNO also significantly inhibited superoxide production, suppressed NF-kB activation, iNOS induction and 3-nitro-tyrosine expression, and up-regulated eNOS expression in the flap vessels. These results suggest that pharmacological suppression of platelet activation may be beneficial for flap survival in case of reperfusion after a prolonged period of flap ischemia.

目 錄
指導教授推薦書………………………………………………….…i
口試委員會審定書…………………………………………………ii
授權書………………………………………………………………iii
簽署人須知…………………………………………………………iv
中文摘要……………………………………………………………vii
英文摘要……………………………………………………………ix
誌謝…………………………………………………………………xi
第一章 綜論…………………………………………………………… 1
1-1論文研究目的及背景相關研究……………………………… 2
1-2 研究假說及計劃目標………………………………………… 9
第二章 材料及方法…………………………………………………… 11
2-1血小板增多有無合併內皮細胞受損對顯微血管吻合成功率的
影響…….……………………………………………………... 12
2-1.1動物模型－次發性血小板增多模型……..……………12
2-1.2血栓性內皮細胞受損模型…………….……………….13
2-1.3實驗設計…………….………………………………….13
2-2調控血小板活化對皮瓣組織缺氧再灌注影響……………….14
2-2.1下腹壁動脈皮瓣組織缺氧再灌注模型………………..15
2-2.2 實驗設計…………….…………………………………15
2-3評估給予一氧化氮(NO)供給者可否調控血小板活化和血
管內皮細胞損傷以提高皮瓣組織經缺氧再灌注存活率……17
2-3.1 實驗設計………….………………………………..….17
2-4評估給予一氧化氮(NO)供給者供應者可否有抗氧化作用並
抑制iNOS誘導機制而提高游離皮瓣成功率………………18
2-4.1 實驗設計…………….…………………………………19
2-5 研究方法…………….……………………………………….20
2-5.1 雷射都卜勒偵測儀……….…………….………………20
2-5.2 流式細胞儀分析血小板活化…………………………..21
2-5.3 流式細胞儀分析新生未成熟血小板…………………..22
2-5.4 血小板凝集試驗 ……….………………….……….… 22
2-5.5 組織染色 …………….……………………….………..23
2-5.6 偵測血漿中NO濃度 …………….…………………...25
2-5.7 西方墨點法（Western blot）分析 …………………...26
2-5.8 偵測氧游離根(O2-)產物 …………….………………...27
2-5.9 準備細胞核萃取物…………….……………………….28
2-5.10 EMSA分析NF-κB活性 ………….…………………29
2-6實驗結果分析及統計…………………………………………30
第三章 結果 …………………………………………………………31
3-1血小板增多合併內皮細胞受損不會影響顯微血管吻合
成功率…………………………………………………………32
3-2給予血小板膜糖蛋白接受體拮抗劑可調控血小板活化並
促進皮瓣組織缺氧再灌注損傷存活率……….……………...34
3-3給予一氧化氮(NO)供給者調控血小板和血管內皮細胞損
傷以提高皮瓣組織缺氧再灌注存活率………………………38
3-4給予一氧化氮 (NO) 供應者可抑制過氧化物引發iNOS
誘導機制而提高游離皮瓣成功率……………………………43
第四章 討論 …………………………………………………………..47
第五章 結論與展望……………………………………………………64
圖表目錄………………………………………………………..………66
參考文獻………………………………………………………………114
附錄……………………………………………………………………133

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